PI: Ferric Fang;Grant # 1R01AI 77629-01A2 Revised Abstract Section Iron is essential for virtually all forms of life and plays a central role in cellular metabolism. Microbes have developed complex strategies for the acquisition, storage, trafficking, utilization and detoxification of iron. One of the primary biochemical roles of iron is to serve as an intermediate electron carrier in oxidative reactions catalyzed by proteins containing iron-sulfur clusters. Our central hypothesis is that innate immunity exploits microbial iron dependence by targeting essential microbial iron and iron-containing proteins with phagocyte-derived reactive oxygen and nitrogen species. This project will examine a novel BaeSR-regulated efflux pump we have discovered which mediates iron excretion when intracellular iron levels are elevated from iron-sulfur cluster damage. The specific aims of this research plan are to analyze the following aspects of the BaeSR system in Salmonella enterica: (1) Activation of BaeSR and characterization of the BaeSR regulon; (2) Identification of the novel chelator responsible for iron efflux; (3) Importance of the BaeSR regulon in iron homeostasis and Salmonella virulence. This work will have fundamental implications for understanding the strategies by which pathogenic microbes evade innate immunity by minimizing iron- dependent cell damage and maintaining iron homeostasis.